In this proposal we study the physiological significance of cell-specific alternative splicing of the voltage-gated N-type calcium channel CaVa1 subunit in nociceptive neurons of the dorsal root ganglia. N- type calcium channels regulate release of glutamate and substance P from primary sensory afferents in the superficial dorsal horn of the spinal cord. The N-type calcium channel is an important target in chronic pain therapy. Inhibition of presynaptic N-type calcium channels is also a therapeutically important site of action of opiates. We recently discovered a unique splice isoform of the N-type calcium channel CaV2.2 subunit, CaV2.2e[37a], that is expressed in many nociceptive neurons. Our recent data show that this unique CaV2.2 splice isoform has unique properties. In this proposal we have two main aims. The first is to understand the physiological significance of alternative splicing of CaV2.2 in regulating the activity of N-type channels in sensory neurons from normal animals. We aim to test the possibility that some of the unique electrical properties and pharmacology of nociceptive neurons originate from cell-specific alternative splicing of CaV2.2 (Aim 1). We will also investigate whether alternative splicing of CaV2.2 is modified following nerve injury using two neuropathic pain models (Aim 2). A change in the pattern of alternative splicing of the N-type channel could have profound effects on the efficacy of synaptic transmission and on the responsiveness of nociceptors to drugs that act by inhibiting the N-type channel. This proposal combines our extensive experience in molecular and electrophysiological studies of calcium channels with that of our collaborator Dr. Carl Saab who has expertise using models of neuropathic pain. We propose that alternative splicing optimizes the behavior and pharmacology of N-type channels in the pain pathway. A defect in alternative splicing following nerve injury could contribute to aberrant pain processing and the de-habilitating symptoms of neuropathic pain. [unreadable] [unreadable]